The hormone, 1α-hydroxylated metabolites of vitamin D—most importantly 1α,25-dihydroxyvitamin D3 and 1α,25-dihydroxyvitamin D2—are known as highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has also been established. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain fluorinated derivatives of 1α,25-dihydroxyvitamin D3, and side chain homologated analogs. Several of these known compounds have been found to exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Paricalcitol is a vitamin D2 derived sterol lacking the carbon-19 methylene group found in all natural vitamin D metabolites. A class of vitamin D-related compounds, namely the 1α-hydroxy-19-nor-vitamin D analogs, as well as a general method for their chemical synthesis, are disclosed in U.S. Pat. No. 4,195,027, EP 0,387,077, U.S. Pat. No. 5,086,191, U.S. Pat. No. 5,237,110, U.S. Pat. No. 5,342,975, U.S. Pat. No. 5,880,113, U.S. Pat. No. 5,587,497, and U.S. Pat. No. 5,710,294. The compounds exhibit pronounced activity in calcium regulation and in arresting the proliferation of undifferentiated cells, including malignant cells, and in inducing their differentiation, and thus represent novel therapeutic agents for the treatment of malignant and other diseases characterized by the proliferative growth of undifferentiated cells. WO 9,103,246 discloses the use of the vitamin D-related compounds to treat the acquired immune deficiency syndrome (AIDS), and its related and derived analogs. EP 0,480,572 discloses compositions containing vitamin D compounds for cosmetic uses. The 19-nor-vitamin D compounds have the formula:
wherein X1 and X2 are each selected from hydrogen, acyl, alkylsilyl and alkoxyalkyl, and where R is selected from alkyl, hydrogen, hydroxyalkyl, said hydroxyalkyl having from 2 to 5 carbon atoms, fluoroalkyl and a side chain of the formula:
wherein R1 represents hydrogen, hydroxy or O-acyl, R2 and R3 are each selected from alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group—(CH2)m—where m is an integer having a value of from 2 to 5, R4 is selected from hydrogen, hydroxy, fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, R5 is selected from hydrogen, fluorine, alkyl, hydroxyalkyl and fluoroalkyl, or R4 and R5 taken together represent double-bonded oxygen, R6 and R7 are each selected from hydrogen, hydroxy, O-acyl, fluorine and alkyl, or, R6 and R7 taken together form a carbon-carbon double bond, and wherein n is an integer having a value of from 1 to 5 and wherein any of the groups —CH(CH3)-, —CH(R7)—, or —CH(R6)— at positions 20, 22 and 23, respectively, may be replaced by an oxygen atom, with the proviso that when n is 2 to 5 each R4 is independently selected from hydrogen, hydroxy, fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, and each R5 is independently selected from hydrogen, fluorine, alkyl, hydroxyalkyl and fluoroalkyl.
Two areas that have been pursued in an effort to identify novel vitamin D compounds with lowered calcemic activity are (1) placement of the hydroxyl group in the side chain on C-24 rather than C-25 and (2) the use of prodrugs (such as Coutts. et al., “A stereospecific synthesis of 24(s)-hydroxyvitamin D2, a prodrug for 1α, 24(S)-dihydroxyvitamin D2”, Organic Process Research & Development. 2002, 6, 246˜255 or U.S. Pat. No. 6,359,012) discloses the first stereospecific synthesis of 24(S)-hydroxyvitamin D2.